Evaluation of 99mTc(i)-tricarbonyl complexes of fluoroquinolones for targeting bacterial infection

Abstract

The aim of this study was to develop (99m)Tc(CO)(3)-labeled fluoroquinolones as novel SPECT radiopharmaceuticals for imaging bacterial infection. Fluoroquinolones, e.g., ofloxacin (OFX), levofloxacin (LVX), lomefloxacin (LMX) and norfloxacin (NFX) were labeled with a fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor. The radiochemical purity of the radiopharmaceuticals exceeded 97% as determined by thin layer chromatography and HPLC. No further purification was necessary before injection. The Re(CO)(3) complex of one of the fluoroquinolones (levofloxacin) was synthesized using [Re(CO)(3)(H(2)O)(3)]OTf and Re(CO)(5)Br precursors in separate experiments and characterized by IR, NMR and mass spectroscopic analysis. These studies revealed the formation of a single species in which the piperazinyl nitrogen and the -COOH group attached to the benzoxazine ring system of quinolone were involved in co-ordination to the Re(CO)(3) core. The HPLC elution pattern and retention time of the Re(CO)(3)-LVX complex were comparable to those of the corresponding (99m)Tc(CO)(3)-complex proving their similarity. When incubated in isotonic saline and serum up to 24 h (99m)Tc(CO)(3)-labeled fluoroquinolones exhibited good in vitro stability. Biodistribution studies performed at different time points on rats intramuscularly infected with S. aureus as well as on rats with sterile inflammation revealed a higher uptake in the infected area than the turpentine induced inflamed area. The uptake in infected thigh was significant with (99m)Tc(CO)(3)-OFX followed by (99m)Tc(CO)(3)-LVX. The mean ratios of the uptake in infected/non-infected thighs were 4.75 and 4.27 at 8 h and 24 h, respectively, for (99m)Tc(CO)(3)-OFX and 4.42 and 4.18 at 24 h and 8 h, respectively, for (99m)Tc(CO)(3)-LVX. The above abscess to muscle ratios were higher than reported for (99m)Tc-ciprofloxacin and other (99m)Tc-labeled fluoroquinolones. Scintigraphy studies also showed a significant uptake in the infectious lesions suggesting that (99m)Tc(CO)(3)-fluoroquinolones might be useful as diagnostic agents for targeted delivery in bacterial infection.

Preclinical evaluation of potential infection‐imaging probe [68Ga]Ga‐DOTA‐K‐A9 in sterile and infectious inflammation

“…The inflammation model was added to evaluate if the imaging agent was able to distinguish between host tissue inflammatory lesions and bacterial infection. Of the 2 methods typically utilized for creating an inflammation model, ie, injection of heat killed bacteria or turpentine oil, the latter method was chosen to gain supplement information about tracer accumulation in sterile inflammatory lesions absent of bacteria or bacterial components. The same postinoculation time was applied for the turpentine‐induced inflammation in mice to align the inflammatory responses of the sterile and infectious tissue lesions.…”

Exploring the Potential of 99mTc(CO)3-Labeled Triazolyl Peptides for Tumor Diagnosis

“…In a separate experiment, the stability of the radiolabeled peptides was also studied by His challenge as per method reported earlier from this laboratory. 14 …”

“…The 99m Tc-labeled peptide and triazolyl peptide were prepared directly from freshly prepared 99m Tc(CO) 3 (H 2 O) 3 precursor. The organometallic precursor 99m Tc(CO) 3 (H 2 O) 3 was synthesized as per method reported earlier from this laboratory 14 and purity was determined by analytical HPLC following the same method as described under synthesis. The peptide solution (0.1 mL) from a stock (2 mg/mL in nitrogen purged water) was added to 0.3 mL of the freshly .…”

Fluoroquinolones as imaging agents for bacterial infection

“…It is +5 with citrate, mercapto-acetylglycylglycylglycine, gluconate, or tetrofosmin. 29–33 Stable complexes with ciprofloxacin and other fluoroquinolones form when 99m Tc is reduced to the +5 oxidation state and a d 2 electronic configuration.…”